Synthesis of Platinum(II) N-Heterocyclic Carbenes Based on Adenosine

Organometallic derivatization of nucleosides is a highly promising strategy for the improvement of the therapeutic profile of nucleosides. Herein, a methodology for the synthesis of metalated adenosine with a deprotected ribose moiety is described. Platinum(II) N-heterocyclic carbene complexes based on adenosine were synthesized, namely N-heterocyclic carbenes bearing a protected and unprotected ribose ring. Reaction of the 8-bromo-2',3',5'-tri-O-acetyladenosine with Pt(PPh₃)₄ by C8-Br oxidative addition yielded complex 1, with a Pt^II centre bonded to C-8 and an unprotonated N7. Complex 1 reacted at N7 with HBF₄ or methyl iodide, yielding protic carbene 2 or methyl carbene 3, respectively. Deprotection of 1 to yield 4 was achieved with NH₄OH. Deprotected compound 4 reacted at N7 with HCl solutions to yield protic NHC 5 or with methyl iodide yielding methyl carbene 6. Protic N-heterocyclic carbene 5 is not stable in DMSO solutions leading to the formation of compound 7, in which a bromide was replaced by chloride. The cis-influence of complexes 1-7 was examined by ³¹P{¹H} and ¹⁹⁵Pt NMR. Complexes 2, 3, 5, 6 and 7 induce a decrease of ¹J_Pt,P of more than 300 Hz, as result of the higher cis-influence of the N-heterocyclic carbene when compared to the azolato ligand in 1 and 4.